Mucous membranes provide a protective layer on the surface of several body cavities, such as the oral cavity, the nasal cavity, the gastrointestinal and respiratory tracts, the vagina, and the bladder. Cells within or glands adjacent to these membranes secrete mucus, a fluid or gel primarily composed of water, lipids, inorganic salts and mucin glycoproteins, which serve to form a protective barrier to inhibit passage of harmful materials to the underlying tissue. There are several diseases and disorders of these mucosal surfaces which can result in severe pain, irritation, erythema, and/or ulceration. Examples of such diseases in the oral cavity include aphthous ulcers, bullous pemphigoid, oral lichen planus, and oral mucous membrane contact dermatitis. Many other ulcerative mucocutaneous diseases are known. There are also painful ulcerative disorders of mucosal surfaces which result as an adverse side-effect in certain therapies, such as chemotherapy and radiation therapy. Mucositis is an adverse side-effect which impacts the oral cavity in patients undergoing therapy for a number of conditions including cancer, AIDS, and in bone marrow transplantation therapy.
Overview of Oral Mucositis
Oral mucositis is a significant problem in patients receiving chemotherapy or radiation therapy. Estimates of oral mucositis in cancer therapy range from 40% of those receiving standard chemotherapy to 76% of bone marrow transplant patients. Virtually all patients who receive radiation therapy to the head and neck area develop oral complications. Mucositis is not only painful, but it also can limit adequate nutritional intake and decrease the willingness of patients to continue treatment. More severe mucositis with extensive ulceration may require costly hospitalizations with parenteral nutrition and narcotics. Mucositis diminishes the quality of life and may result in serious clinical complications. A healthy oral mucosa serves to clear microorganisms and provides a chemical barrier that limits penetration of many compounds into the epithelium. A mucosal surface that is damaged increases the risk of a secondary infection and may even prove to be a nidus for systemic infection. Mucositis may result in the need to reduce dosage in subsequent chemotherapy cycles or to delay radiation therapy, which may ultimately affect patient response to therapy.
Normally, cells of the mouth undergo rapid renewal over a 7- to 14-day cycle. Both chemotherapy and radiation therapy interfere with cellular mitosis and reduce the ability of the oral mucosa to regenerate. Cancer chemotherapeutic drugs that produce direct stomatotoxicity include the alkylating agents, antimetabolites, natural products, and other synthetic agents such as hydroxyurea and procarbazine hydrochloride. Typical sequelae of these cytotoxic agents include epithelial hyperplasia, collagen and glandular degeneration, and epithelial dysplasia. Mucositis is an inevitable side effect of radiation. The severity of the mucositis is dependent on the type of ionizing radiation, the volume of irradiated tissue, the dose per day, and the cumulative dose. As the mucositis becomes more severe, pseudo membranes and ulcerations develop. Poor nutritional status further interferes with mucosal regeneration by decreasing cellular migration and renewal.
Direct stomatotoxicity is usually seen 5 to 7 days after the administration of chemotherapy or radiation therapy. In the nonmyelosuppressed patient, oral lesions heal within 2 to 3 weeks. The no keratinized mucosa is most affected. The most common sites include the labial, buccal, and soft palate mucosa, as well as the floor of the mouth and the ventral surface of the tongue. Clinically, mucositis presents with multiple complex symptoms. It begins with asymptomatic redness and erythema and progresses through solitary white elevated desquamative patches that are slightly painful to contact pressure. Following these large, acutely painful contiguous pseudo membranous lesions will develop with associated dysphagia and decreased oral intake. Histopathologically, edema of the retepegs is noted, along with vascular changes that demonstrate a thickening of the tunica intima with concomitant reduction in the size of the lumen and destruction of the elastic and muscle fibers of the vessel walls. The loss of the epithelial cells to the basement membrane exposes the underlying connective tissue stroma with its associated innervation, which, as the mucosal lesions enlarge, contributes to increasing pain. Oral infections, which may be due to bacteria, viruses, or fungal organisms, can further exacerbate the mucositis as well as lead to systemic infections. If the patient develops both severe mucositis and thrombocytopenia, oral bleeding may occur that is very difficult to treat.
A mucositis grading system gives the physician the ability to assess the severity of the mucositis in terms of both the pain and the patient's ability to maintain adequate nutrition so that a treatment plan can be appropriately constructed. There are many different grading systems; most are based on two or more clinical parameters, including erythema, pain, and problems with eating. An example of a common grading system is that proposed by the National Cancer Institute, which uses a numbering scale of 0 to 4. Grade 0 means no mucositis; grade 1, the patient has painless ulcers, erythema, or mild soreness; grade 2, the patient has painful erythema, edema, or ulcers but can eat; grade 3, the patient has painful erythema, edema, or ulcers and cannot eat; and grade 4, the patient requires parenteral or enteral support.                (source: DeVita: Cancer: Principles and Practice of Oncology, 5th ed., Copyright© 1997 Lippincott-Raven Publishers)Current Methods for the Prevention and Treatment for Mucositis        
In spite of the significance of the problem, there are currently no well-established procedures and formulations for the prevention and treatment of mucositis. As a result, there is no standardized approach, and many institutes have adopted treatment regimens based on little or no supporting data of safety and efficacy. There is even disagreement on whether good oral hygiene is beneficial (for example: Dodd M J, Miaskowski C, Shiba G H, Dibble S L, Greenspan D, MacPhail L, Paul S M, Larson P, Risk factors for chemotherapy-induced oral mucositis: dental appliances, oral hygiene, previous oral lesions, and history of smoking, Cancer Invest 1999;17(4):278–84 and Cheng K K, Molassiotis A, Chang A M, Wai W C, Cheung S S. Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in pediatric cancer patients, Eur J Cancer 2001 November;37(16):2056–6). Good oral hygiene is typically recommended, supplemented by formulations which are compounded locally and primarily used to provide prophylaxis. Thus, patients will be asked to use ice, saline rinses, bicarbonate rinses, or rinse with antimicrobial formulations such as acyclovir or chlorhexidine. (Fulton J S, Middleton G J, McPhail J T, Management of oral complications, Semin Oncol Nurs 2002 February;18(1):28–35). Regimens commonly used for the treatment of mucositis and its associated pain include a local anesthetic such as lidocaine or Dyclone, Maalox or Mylanta, diphenhydramine (Benadryl), nystatin, or sucralfate. These agents are either used alone or in different combinations of the above medications made into a mouthwash. Other agents used less commonly include Kaopectate, allopurinol, vitamin E, beta-carotene, Kamillosan liquid, aspirin, antiprostaglandins, prostaglandins, silver nitrate, and antibiotics. Oral and sometimes parenteral narcotics are used for pain relief. (DeVita: Cancer: Principles and Practice of Oncology, 5th ed., Copyright© 1997 Lippincott-Raven Publishers). Recent reviews of current treatment options and of investigational clinical trials indicated that most agents and options failed to show any benefit in the prevention and/or treatment of mucositis. (Worthington H V, Clarkson J E, Eden O B, Interventions for treating oral mucositis for patients with cancer receiving treatment, Cochrane Database Syst Rev 2002;(1): CD001973; Demarosi F, Bez C, Carrassi A., Prevention and treatment of chemo- and radiotherapy-induced oral mucositis. Minerva Stomatol 2002 May;51(5):173–86).
A recent review (Sonis S T, Fey E G, Oral Complications of Cancer Therapy, Oncology 2002, 16:680–695) provides an overview of the many agents which have been evaluated in clinical studies for the prevention and treatment of mucositis, and concludes “there is no effective approved treatment for mucositis”, and that there is no conclusive evidence that experimental agents which are currently the subjects of clinical studies will provide benefit to future patients. While ongoing studies are providing a better understanding of the etiology of mucositis, it may be some time before this knowledge can be translated into effective new treatments. In the meantime, the main approaches are based upon theory, and it is anticipated that it may be many years before rationale drug design can be applied based upon a better understanding of etiology.
The current approaches can be classified as “palliative, cytoprotective, anti-inflammatory, and antimicrobial agents, and cytokines” (Plevova P: Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: A review. Oral Oncol 35:453–470, 1999; Sonis S T, Fey E G, Oral Complications of Cancer Therapy, Oncology 2002, 16:680–695).
Examples of each type are:
    i) Palliative: saline and bicarbonate rinses, sucralfate suspensions, and topical analgesics (for example, viscous lidocaine, dyclonine, diphenhydramine, and loperamide.    ii) Cytoprotective: Ice chips, allopurinol, glutamine, pentoxifylline, Ethyol, and antioxidants such as vitamins C and E.    iii) Anti-inflammatories: Benzydamine, indomethacin, and amlexanox.    iv) Anti-microbials: chlorhexidine, povidone iodine, the protegrin IB-367.    v) Cytokines: Keratinocyte growth factor, transforming growth factor-beta 3, and interleukin-11, and the colony-stimulating factors: G-CSF and GM-CSF.
Topical coating agents such as magnesium hydroxide (e.g., Milk of Magnesia), Kaopectate (Pharmacia & Upjohn, Columbus, Ohio), OraRinse (Carrington Laboratories), GelClair (Sinclair Pharmaceuticals) and aluminum hydroxide gel (Amphojel; Wyeth-Ayerst, Philadelphia, Pa.) may provide some symptomatic relief of the lesions associated with mucositis (J B Epstein, A W Chow, Oral complications associated with immunosuppression and cancer therapies, Infectious Disease Clinics of North America, 1999, 13(4), 901–923).
While palliation provides temporary relief, none of the above treatments provides any proven benefit in preventing or treating mucocitis, with the possible exception of the use of ice chips during 5-FU therapy. Therefore, the development of a product which provides clinically proven benefit for the prevention and/or treatment of mucositis remain a major unmet medical need.